The present invention provides compounds that are active at metabotropic glutamate receptors, particularly compounds that are active as antagonists at metabotropic glutamate receptors, more particularly at the mGluR5 glutamate receptor.
Recent advances in the elucidation of the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the therapy of acute and chronic neurological and psychiatric disorders and diseases. However, the major challenge to the realization of this promise has been the development of metabotropic glutamate receptor subtype-selective compounds.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate produces its effects on central neurons by binding to and thereby activating cell surface receptors. These receptors have been divided into two major classes, the ionotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
The metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that activate a variety of intracellular second messenger systems following the binding of glutamate. Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).
Eight distinct mGluR subtypes, termed mGluR1 through mGluR8, have been identified by molecular cloning. See, for example, Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosci. 15:3970 (1995).
Metabotropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group III mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics. Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995).
Group I mGluRs comprise mGluR1, mGluR5, and their alternatively spliced variants. The binding of agonists to these receptors results in the activation of phospholipase C and the subsequent mobilization of intracellular calcium. Electrophysiological measurements have been used to demonstrate these effects, for example, in Xenopus oocytes that express recombinant mGluR1 receptors. See, for example, Masu et al., Nature 349:760 (1991); Pin et al., PNAS 89:10331 (1992). Similar results have been achieved with oocytes expressing recombinant mGluR5 receptors. Abe et al., J. Biol. Chem. 267:13361 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosci. 15:3970 (1995). Alternatively, agonist activation of recombinant mGluR1 receptors expressed in Chinese hamster ovary (CHO) cells stimulates PI hydrolysis, cAMP formation, and arachidonic acid release as measured by standard biochemical assays. Aramori et al., Neuron 8:757 (1992).
By comparison, the activation of mGluR5 receptors, expressed in CHO cells, stimulates PI hydrolysis and subsequent intracellular calcium transients, but no stimulation of cAMP formation or arachidonic acid release is observed. Abe et al., J. Biol. Chem. 267:13361 (1992). However, activation of mGluR5 receptors expressed in LLC-PK1 cells results in PI hydrolysis and increased cAMP formation. Joly et al., J. Neurosci. 15:3970 (1995). The agonist potency profile for Group I mGluRs is quisqualate greater than glutamate=ibotenate greater than (2S, 1xe2x80x2S,2xe2x80x2S)-2-carboxycyclopropyl)glycine (L-CCG-I) greater than (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). Quisqualate is relatively selective for Group I receptors, as compared to Group II and Group III mGluRs, but it also is a potent activator of ionotropic AMPA receptors. Pin et al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417 (1995).
The lack of subtype-specific mGluR agonists and antagonists has impeded elucidation of the physiological roles of particular mGluRs, and the mGluR-associated pathophysiological processes that affect the CNS have yet to be defined. However, work with the available non-specific agonists and antagonists has yielded some general insights about the Group I mGluRs as compared to the Group II and Group III mGluRs.
Attempts at elucidating the physiological roles of Group I mGluRs suggest that activation of these receptors elicits neuronal excitation. Various studies have demonstrated that ACPD can produce postsynaptic excitation upon application to neurons in the hippocampus, cerebral cortex, cerebellum, and thalamus, as well as other brain regions. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested that activation of presynaptic mGluRs occurs, resulting in increased neurotransmitter release. Baskys, Trends Pharmacol. Sci. 15:92 (1992); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).
Pharmacological experiments implicate Group I mGluRs as the mediators of this excitatory mechanism. The effects of ACPD can be reproduced by low concentrations of quisqualate in the presence of ionotrophicGluR antagonists. Hu et al., Brain Res. 568:339 (1991); Greene et al., Eur. J. Pharmacol. 226:279 (1992). Two phenylglycine compounds known to activate mGluR1, namely (S)-3-hydroxyphenylglycine ((S)-3HPG) and (S)-3,5-dihydroxyphenylglycine ((S)-DHPG), also produce excitation. Watkins et al., Trends Pharmacol. Sci. 15:33 (1994). In addition, the excitation can be blocked by (S)-4-carboxyphenylglycine ((S)-4CPG), (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG), and (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), compounds known to be mGluR1 antagonists. Eaton et al., Eur. J. Pharmacol. 244:195 (1993); Watkins et al., Trends Pharmacol. Sci. 15:333 (1994).
Metabotropic glutamate receptors have been implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term depression. Bashir et al., Nature 363:347 (1993); Bortolotto et al., Nature 368:740 (1994); Aiba et al., Cell 79:365 (1994); Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nociception and analgesia also has been demonstrated. Meller et al., Neuroreport 4: 879 (1993). In addition, mGluR activation has been suggested to play a modulatory role in a variety of other normal processes including synaptic transmission, neuronal development, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waking, motor control, and control of the vestibulo-ocular reflex. Generally, see Nakanishi, Neuron 13: 1031 (1994); Pin et al., Neuropharmacology 34:1; Knopfel et al., J. Med. Chem. 38:1417 (1995).
Metabotropic glutamate receptors also have been suggested to play roles in a variety of pathophysiological processes and disease states affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, and neurodegenerative diseases such as Alzheimer""s disease. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Cunningham et al., Life Sci. 54:135 (1994); Hollman et al., Ann. Rev. Neurosci. 17:31 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995). Much of the pathology in these conditions is thought to be due to excessive glutamate-induced excitation of CNS neurons. Because Group I mGluRs appear to increase glutamate-mediated neuronal excitation via postsynaptic mechanisms and enhanced presynaptic glutamate release, their activation probably contributes to the pathology. Accordingly, selective antagonists of Group I mGluR receptors could be therapeutically beneficial, specifically as neuroprotective agents, analgesics, or anticonvulsants.
Preliminary studies assessing therapeutic potentials with the available mGluR agonists and antagonists have yielded seemingly contradictory results. For example, it has been reported that application of ACPD onto hippocampal neurons leads to seizures and neuronal damage (Sacaan et al., Neurosci. Lett. 139:77 (1992); Lipparti et al., Life Sci. 52:85 (1993). Other studies indicate, however, that ACPD inhibits epileptiform activity, and also can exhibit neuroprotective properties. Taschenberger et al., Neuroreport 3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh et al., Proc. Natl. Acad. Sci. USA 88:9431 (1991); Chiamulera et al., Eur. J. Pharmacol. 216:335 (1992); Siliprandi et al., Eur. J. Pharmacol. 219:173 (1992); Pizzi et al., J. Neurochem. 61:683 (1993).
It is likely that these conflicting results are due to the lack of selectivity of ACPD, which causes activation of several different mGluR subtypes. In the studies finding neuronal damage it appears that Group I mGluRs were activated, thereby enhancing undesirable excitatory neurotransmission. In the studies showing neuroprotective effects it appears that activation of Group II and/or Group III mGluRs occurred, inhibiting presynaptic glutamate release, and diminishing excitatory neurotransmission.
This interpretation is consistent with the observation that (S)-4C3HPG, a Group I mGluR antagonist and Group II mGluR agonist, protects against audiogenic seizures in DBA/2 mice, while the Group II mGluR selective agonists DCG-IV and L-CCG-I protect neurons from NMDA- and KA-induced toxicity. Thomsen et al., J. Neurochem. 62:2492 (1994); Bruno et al., Eur. J. Pharmacol. 256:109 (1994); Pizzi et al., J. Neurochem. 61:683 (1993).
Based on the foregoing, it is clear that a lack of potency and selectivity limits the value of the mGluR agonists and antagonists now available. In addition, most currently available compounds are amino acids or amino-acid derivatives which have limited bioavailabilities, thereby hampering in vivo studies to assess mGluR physiology, pharmacology, and therapeutic potential. On the other hand, compounds that selectively inhibit activation of metabotropic glutamate receptor Group I subtypes are indicated for treatment of neurological disorders and diseases such as senile dementia, Parkinson""s disease, Alzheimer""s disease, Huntington""s Chorea, pain, epilepsy, head trauma, anoxic and ischemic injuries, and psychiatric disorders such as anxiety, schizophrenia and depression.
Accordingly, a need exists for potent mGluR agonists and antagonists that display a high selectivity for a mGluR subtype, particularly a Group I receptor subtype.
The present invention, provides metabotopic glutamate receptor-active compounds, which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and processes of making these compounds.
Further, this invention provides pharmaceutical compositions containing compounds which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods of making these pharmaceutical compositions.
Another aspect of the invention is to provide methods of inhibiting activation of an mGluR Group I receptor, specifically mGluR5. In particular, a medical condition associated with metabotropic glutamate receptors includes: stroke; head; trauma; anoxic; injury; ischemic; injury; hypoglycemia; epilepsy; pain; migraine headaches; Parkinson""s disease; senile dementia; Huntington""s Chorea; and Alzheimer""s disease.
The invention provides methods of treating a disease associated with excitatory activation of an mGluR Group I receptor and of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, specifically wherein the mGluR Group I receptor is mGluR5 Finally, the present invention provides potent antagonists of Group I mGluRs, specifically mGluR5.
According to a first aspect of the invention, these antagonists may be represented by compounds of the general formula:
Ar1xe2x80x94Lxe2x80x94Ar2 
wherein Ar1 is an optionally substituted heteroaromatic moiety and Ar2 is an optionally substituted benzene ring. The L moiety is a group that not only covalently binds to the Ar1 and Ar2 moieties, and facilitates adoption of the correct spatial orientation of Ar1 and Ar2, but also itself may interact with the protein, to effect receptor binding.
In one embodiment of the invention, L is selected from the group consisting of xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CONHCH2xe2x80x94, xe2x80x94CH2CONHxe2x80x94, xe2x80x94CNHNHxe2x80x94, xe2x80x94CNHNHCH2xe2x80x94, xe2x80x94C xe2x95x90NOxe2x80x94CH2xe2x80x94, xe2x80x94CH2NHCH2xe2x80x94, xe2x80x94CH2CH2NHxe2x80x94, xe2x80x94NHCH2COxe2x80x94, xe2x80x94NHCH2CHOHxe2x80x94, xe2x80x94NHCNHNH.xe2x80x94, xe2x80x94NHCONHxe2x80x94, cyclopentane, cyclopentadiene, furan, thiofuran, pyrrolidine, pyrrole, 2-imidazoline, 3-imidazoline, 4-imidazoline, imidazole, pyrazoline, pyrazolidine, imidazolidine, oxazole, 2-oxazole, thiazole, isoxazole, isothiazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole, 1,2,4-oxathiazole, 1,3,4-oxathiazole, 1,4,2-dioxazole, 1,4,2-oxathiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1H-tetrazole, cyclohexane, piperidine, tetrahydropyridine, 1,4-dihydropyridine, pyridine, benzene, tetrahydropyran, 3,4-dihydro-2H-pyran, 2H-pyran, 4H-pyran, tetrahydrothiopyran, 3,4-dihydro-2H-thiopyran, 2H-thiin, 4H-thiopyran, morpholine, thiomorpholine, piperazine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,2,3-triazine, 1,3,5-triazine, and 1,2,4,5-tetrazine.
In another embodiment of the invention, Ar1 is selected from the group consisting of phenyl, benzyl, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl, and Ar2 is selected from the group consisting of thiazoyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrroyl, imidazoyl, pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazoyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, and chromenyl.
According a second aspect of the invention, these antagonists may be represented by compounds of Formula I: 
wherein
---- represents a double or single bond;
X, Y, and Z are independently selected from the group consisting of: N; O; S;
and CR1 and at least one of X, Y, and Z is a heteroatom;
wherein
R1 is selected from the group consisting of: H; alkyl; xe2x80x94CF3; xe2x80x94OR2; xe2x80x94SR2; xe2x80x94NR2R3; xe2x95x90O; xe2x95x90S; xe2x95x90NR2; and xe2x95x90CR2R3; and
wherein
R2 and R3 may be independently selected from the group consisting of: H; alkyl; haloalkyl; alkyloxy; alkylamine; cycloalkyl;
heterocycloalkyl; aryl; heteroaryl; alkylaryl; alkylheteroaryl; haloaryl;
alkyloxyaryl; alkenylaryl; alkenyloxyaryl; and haloheteroaryl; and Ar1 and Ar2 are independently selected from the group consisting of: aryl and heteroaryl, and at least one of Ar1 and Ar2 is substituted with at least one substituent G;
wherein
G is selected from the group consisting of: haloalkyl; heteroaryl;
cycloalkene; alkenyl; alkynyl; A-alkenyl; A-alkynyl; alkyloxy; A-alkyloxy; xe2x80x94R2OR3; xe2x80x94R2OC(O)R3; (CH2)mxe2x80x94NR2R3; xe2x80x94OCH2CH(Cl)CH2Cl; and substituted aryl wherein the aryl substituent is R4, and
wherein
A is a linker selected from the group consisting of: CH2O; NH; S;
SO; SO2 ; NSO2 ; OSO2 ; and xe2x80x94C(NR2)NR3;
m is selected from 0 and 1; and
R4 is selected from the group consisting of: halo; xe2x80x94OR2; xe2x80x94SR2; xe2x80x94SOR2; xe2x80x94SO2R2; xe2x80x94SO2NR2R3; xe2x80x94R2OR3; xe2x80x94R2SR3; xe2x80x94OCOR2; xe2x80x94OCONR2R3; xe2x80x94NR2COR3; xe2x80x94NR2CO2R3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(NR2)NR3; xe2x80x94CO2R2R3; xe2x80x94CONR2R3;
xe2x80x94C(O)R2; xe2x80x94CH(OR2)R3; xe2x80x94CH2(OR2); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR2R3; NR2R3; aryl;
aralkyl; heteroaryl; and heteroaralkyl; and
Ar1, Ar2, and the substituent G are optionally further substituted with one or more substituents selected independently from the group consisting of R2 and R4;
with the proviso that when ---- represents a double bond, then either of Ar1 or
Ar2 is pyridyl and the compound is not:
3-(2-Pyridyl)-5-(2-nitrophenyl)-1,2,4-oxadiazole,
3-(2-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole,
3-(4-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole
3-(3-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole,
3-(4-Pyridyl)-5-(4-chlorophenyl)-1,2,4-oxadiazole,
3-(2-Pyridyl)-5-(3-ethoxyphenyl)-1,2,4-oxadiazole,
3-(2-Pyridyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole,
3-(2-Pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole,
3-(2-chlorophenyl)-5-(4-pyridyl)-1,2,4-oxadiazole,
3-(2-ethoxyphenyl)-5-(3-pyridyl)-1,2,4-oxadiazole,
3-styryl-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(3-Pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole,
3-(3-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole,
3-(4-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole,
3-(3-Pyridyl)-5-(2-pyridyl)-1,2,4-oxadiazole,
3-(4-Pyridyl)-5-(3-pyridyl)-1,2,4-oxadiazole,
3-(4-Pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole,
3-(2-ethyl-4-pyridyl)-5-(2-hydroxyphenyl)-1,2,4-oxadiazole,
3-(2-ethyl-4-pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole,
3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole,
3-(2-ethyl-4-pyridyl)-5-(4-chlorophenylmethyl)-1,2,4-oxadiazole,
3-(2-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole,
3-(2-pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole,
3-(3-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole,
3-(3-pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole,
3-(2-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole,
3-(4-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole,
3-(2-pyridyl)-5-phenyl-1,2,4-oxadiazole,
2-(4-methoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,
3-(2-pyridyl)-5-(2-chlorophenyl)-1,2,4,-triazole,
3-(2-pyridyl)-5-(2,6-dichlorophenyl)-1,2,4,-triazole,
2-(2-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy)phenyl]-furan,
2-(3-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy)phenyl]-furan, or
2-(4-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxyphenyl)]-furan.
In another aspect of the invention, antagonists of Formula II are provided. 
wherein
---- represents a double or single bond;
X2 is selected from N and C, and Y2 is selected from the group consisting of: N;
O; S; and CR5, and at least one of X2 and Y2 is a heteroatom;
wherein
R5 is selected from the group consisting of: H; alkyl; xe2x80x94CF3; xe2x80x94OR6; xe2x80x94SR6;
NR6R7; xe2x95x90O; xe2x95x90S; xe2x80x94xe2x95x90NR6; and xe2x95x90CR6R7; and
wherein
R6 and R7 may be independently selected from the group consisting of: H; alkyl; haloalkyl; alkyloxy; alkylamine; cycloalkyl;
heterocycloalkyl; aryl; heteroaryl; alkylaryl; alkylheteroaryl; haloaryl;
alkyloxyaryl; alkenylaryl; alkenyloxyaryl; and haloheteroaryl; and
Ar3 and Ar4 are independently selected from the group consisting of aryl and heteroaryl and one, or both, of Ar3 and Ar4 is optionally substituted with one or more substituents G2;
wherein
G2 is selected from the group consisting of: haloalkyl; heteroaryl;
cycloalkene; alkenyl; alkynyl; A-alkenyl; A-alkynyl; alkyloxy; A-alkyloxy; xe2x80x94R6OR7; xe2x80x94R6OC(O)R7; (CH2)mxe2x80x94NR6R7; xe2x80x94OCH2CH(Cl)CH2Cl; and substituted aryl wherein the aryl substituent is R8; and
wherein
A is a linker selected from the group consisting of: CH2O; NH; S; SO; SO2; NSO2; OSO2 ; and xe2x80x94C(NR6)NR7;
m is selected from 0 and 1; and
R8 is selected from the group consisting of: halo; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94SOR6; xe2x80x94SO2R6; xe2x80x94SO2NR6R7; xe2x80x94R6OR7 R6SR7; xe2x80x94OCOR6; xe2x80x94OCONR6R7; xe2x80x94NR6COR7; xe2x80x94NR6CO2R7; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(NR6)NR7; xe2x80x94CO2R6R7; xe2x80x94CONR6R7;
xe2x80x94C(O)R6; xe2x80x94CH(OR6)R7; xe2x80x94CH2(0R6); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR6R7; NR6R7; aryl;
aralkyl; heteroaryl; and heteroaralkyl; and
Ar3, Ar4, and the substituent G2 are optionally further substituted with one or more substituents selected independently from the group consisting of: R6 and R8.
Another aspect of the invention is to provide processes for making the compounds of the present invention.
A further aspect of the invention is to provide a method of inhibiting activation of an mGluR Group I receptor, specifically mGluR5, comprising treating a cell containing said mGluR Group I receptor with an effective amount of a compound of the present invention.
Yet another aspect of the invention is to provide a method of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, in particular mGluR5, comprising treating neurons with an effective amount of a compound of the present invention.
A further aspect of the invention is to provide a method of treating a disease associated with Group I mGluR activation or amenable to therapeutic intervention with a mGluR Group I antagonist, for example, a disease associated with glutamate-induced neuronal damage, which method comprises the step of administering to a patient, in need of such treatment, for example, a patient suffering from said disease, or at risk of suffering from said disease, a therapeutically effective non-toxic amount of a compound of the present invention. In a particular aspect of the invention a therapeutically effective amount of the present invention would be an amount which selectively antagonizes an mGluR Group I receptor, in particular the mGluR5 receptor.
Other aspects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
The term xe2x80x9calkylxe2x80x9d as used herein refers to straight- and branched-chain alkyl radicals containing from 1, 2, 3, 4, 5, or 6 carbon atoms and includes methyl, ethyl and the like.
The term xe2x80x9carylxe2x80x9d as used herein refers to a monocyclic aromatic group such as phenyl and the like or a benzo-fused aromatic group such as indanyl, naphthyl, fluorenyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic compounds containing one or more hetero atoms such as pyridyl, furyl, thienyl and the like or a benzofused aromatic containing one or more heteroatoms such as indolyl, quinolinyl and the like.
The term xe2x80x9cheteroatomxe2x80x9d as used herein refers to non-carbon atoms such as N, O, S and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a carbocyclic ring containing of 3, 4, 5, 6, 7, or 8 carbons and includes cyclopropyl, cyclohexyl and the like.
The term xe2x80x9cheterocycloalkylxe2x80x9d as used herein refers to 3, 4, 5, 6, 7, or 8 membered rings containing 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O and includes piperidine, piperizine, pyran and the like.
The term xe2x80x9chaloxe2x80x9d as used herein refers to the halogen radicals fluoro, chloro, bromo, and iodo.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to an alkyl substituted with one or more halogens, such as bromoethyl, chloromethyl, trichloromethyl and the like.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to a straight- or branched-chain alkoxy containing 1, 2, 3, 4, 5 or 6 carbon atoms and includes methoxy, ethoxy and the like.
The term xe2x80x9calkyloxyxe2x80x9d as used herein refers to an alkyl substituted with a hydroxy group such as hydroxyethyl, hydroxypropyl and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a straight or branched-chain alkyl containing one or more double bonds such as propenyl, vinyl and the like.
The term xe2x80x9caralkylxe2x80x9d as used herein refers to an alkyl substituted with an aryl such as benzyl, phenethyl and the like.
The term xe2x80x9calkylaminexe2x80x9d as used herein refers to an alkyl substituted with an amine such as aminomethyl, or dimethylaminoethyl and the like.
The term xe2x80x9calkylarylxe2x80x9d as used herein refers to an aryl substituted with an alkyl group such as methylphenyl, isopropylnaphthyl and the like.
The term xe2x80x9calkylheteroarylxe2x80x9d as used herein refers to a heteroaryl substituted with an alkyl group. Particular examples include methylpyridine, ethylfuran, and the like.
The term xe2x80x9calkynylxe2x80x9d as used herein refers to a straight or branched-chain alkyl containing one or more double bonds such as ethynyl, propynyl, vinyl and the like.
The term xe2x80x9chaloarylxe2x80x9d as used herein refers to an aryl substituted with a halogen such as bromophenyl, chlorophenyl and the like.
The term xe2x80x9calkyloxyarylxe2x80x9d as used herein refers to an aryl substituted with an alkyloxy group such as hydroxyethylphenyl and the like.
The term xe2x80x9calkenyloxyarylxe2x80x9d as used herein refers to an aryl susbtituted with an alkenyloxy group such as propenyloxy phenyl and the like.
The term xe2x80x9chaloheteroarylxe2x80x9d as used herein refers to a heteroaryl substituted with a halogen. A particular example is 4-chloropyridine.
The term xe2x80x9ccycloalkenexe2x80x9d as used herein refers to a 3, 4, 5, 6, 7, or 8-member ring, which contains one or more double bonds, and may contain a heteroatom. Particular examples include cyclohexene, tetrahydropyridine and the like.
The term xe2x80x9calkenylarylxe2x80x9d as used herein refers to an aryl substituted with an alkenyl group. A particular example is vinyl benzene.
The present invention provides compounds that are potent and selective antagonists of mGluR5. The compounds contemplated by the invention can be represented by the general formula:
Ar1xe2x80x94Lxe2x80x94Ar2 
where Ar1 is an optionally substituted heterocyclic moiety and Ar2 is an optionally substituted carbocyclic moiety. The G moiety is a group that not only covalently binds to the Ar1 and Ar2 moieties and facilitates adoption of the correct spatial orientation of Ar1 and Ar2, but may itself interact with the protein to allow receptor binding.
The Ar1 moiety is generally defined as a heterocyclic moiety, and the Ar2 moiety is generally defined as a carbocylic moiety. Ar1 and Ar2 can be monocyclic or fused bicyclic groups. Ar2 is preferably defined as an aryl or alkaryl moiety. Ar1 is preferably defined as a heterocyclic, heteroaryl or heteroarylalkyl moiety. The ring systems encompassed by Ar1 can contain up to four heteroatoms, independently selected from the group consisting of N, S, and O. When Ar1 is a heteroaryl ring or ring system, it preferably contains one or two heteroatoms. At least one of the heteroatoms preferably is nitrogen (N). The heterocyclic or fused heterocylic moiety preferably is selected from the group consisting of quinolyl, quinazolyl, quinoxalyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and pyrazyl.
Monocyclic Ar1 groups include, but are not limited to: thiazoyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrroyl, imidazoyl, pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl moieties. Monocyclic Ar2 group include but are not limited to phenyl and benzyl. Fused bicyclic Ar2 include, but are not limited to, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl. Fused bicyclic Ar1 groups include, but are not limited to: benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazoyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, and chromenyl moieties. Ar1 preferably is a 2-pyridyl moiety. Ar2 preferably is a substituted phenyl moiety.
The Ar1 and Ar2 moieties optionally may independently be substituted with one or more moieties selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 O-alkyl, xe2x80x94OH, xe2x80x94OCF3, xe2x80x94COOR, xe2x80x94COR, xe2x80x94SOR, xe2x80x94SO2NRRxe2x80x2, xe2x80x94NRRxe2x80x2, xe2x80x94CN, xe2x80x94CF3,xe2x80x94COxe2x80x94NRRxe2x80x2, xe2x80x94Axe2x80x94(CH2)nxe2x80x94NRRxe2x80x2, wherein A is C, O, N, SO, SO2 , and R and Rxe2x80x2 are independently selected from the group consisting of C1-C3 alkyl, H, cycloalkyl, heterocycloalkyl, aryl, and n is 1, 2, 3, or 4.
The L moiety is generally made up of 1-14 atoms. L can be independently selected from the group of atoms: C, H, N, O, and S.
The L moiety can thus be made of a non-cyclic moiety. Several examples of these are xe2x80x94NHxe2x80x94 (amine), xe2x80x94Sxe2x80x94 (thioether), xe2x80x94Oxe2x80x94 (ether), xe2x80x94COxe2x80x94 (ketone), xe2x80x94CONHxe2x80x94 (amide), xe2x80x94CONHCH2xe2x80x94, xe2x80x94CH2CONHxe2x80x94, xe2x80x94CNHNHxe2x80x94 (amidine), xe2x80x94CNHNHCH2xe2x80x94, xe2x80x94Cxe2x95x90NOxe2x80x94CH2xe2x80x94 (methoxime), xe2x80x94CH2NHCH2xe2x80x94, xe2x80x94CH2CH2NHxe2x80x94, xe2x80x94NHCH2COxe2x80x94, xe2x80x94NHCH2CHOHxe2x80x94, xe2x80x94NHCNHNH.xe2x80x94 (guanidine), and xe2x80x94HCONHxe2x80x94 (urea), for example.
The atomic arrangement in the L moiety can also be made to form a five-membered ring. Several examples of these are cyclopentane, cyclopentadiene, furan, thiofuran, pyrrolidine, pyrrole, 2-imidazoline, 3-imidazoline, 4-imidazoline, imidazole, pyrazoline, pyrazolidine, imidazolidine, oxazole, 2-oxazole, thiazole, isoxazole, isothiazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole, 1,2,4-oxathiazole, 1,3,4-oxathiazole, 1,4,2-dioxazole, 1,4,2-oxathiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, and 1H-tetrazole, for example. The 1,2,4-oxadiazole is most preferred.
The atomic arrangement in the L moiety can also be made to form a six-membered ring. Several examples of these are cyclohexane, piperidine, tetrahydropyridine, 1,4-dihydropyridine, pyridine, benzene, tetrahydropyran, 3,4-dihydro-2H-pyran, 2H-pyran, 4H-pyran, tetrahydrothiopyran, 3,4-dihydro-2H-thiopyran, 2H-thiin, 4H-thiopyran, morpholine, thiomorpholine, piperazine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,2,3-triazine, 1,3,5-triazine, and 1,2,4,5-tetrazine, for example.
The atomic arrangement in the L moiety can also be made to form a five- or six-membered ring containing one or more carbonyl groups. Several examples of these are 2-azetidinone, 1,2-diazetidin-3-one, cyclopentanone, 2-cyclopentenone, 2-pyrrolidinone, 3-pyrrolin-2-one, succinimide, maleimide, 3-pyrazolidinone, 2-imidazolidone, 4-imidazolin-2-one, 2H-imidazol-2-one, 4-imidazolinone, 3-pyrazolin-5-one, hydantoin, 1H-imidazole-2,5-dione, 2-oxazoline-4-one, 2-oxazolidinone, 3-oxazolin-5-one, 3(2H)-isoxazolone, 2,4-oxazolidinedione, 1,2,4-triazoline-3,5-dione, 2,4-dihydro-3H-1,2,4-triazol-3-one, 2H-pyran-2-one, 2(1H)-pyridone, 2(1H)-pyrazinone, 4(3H)-pyrimidone, 3,4-dihydropyrimidin-4-one, glutarimide, 4,6-(1H,5H)-pyrimidinedione, 1,3,5-triazin-2(1H)-one, and cyanuric acid, for example.
In a preferred embodiment, L comprises a heterocyclic 5-membered ring system. Preferably, L is an oxazole or an 1,2,4-oxadiazole ring. The L moiety may have either one of two possible orientations with respect to the Arl and Ar2 groups. Thus, for example, the invention prefers compounds having the configuration 4-(Ar1)-2-(Ar2)-oxazole or 3-(Ar1)-5-(Ar2)-1,2,4-oxadiazole.
According to one aspect of the invention, compounds of Formula I are provided. 
Formula I contains a five member ring containing three variables X, Y, and Z. There are attached to this five member ring two substituents, Ar1 and Ar2. The five member ring may contain 0, 1 or 2 double bonds as denoted by the dotted lines in Formula 1. In a preferred embodiment of the invention, the five member ring has 2 double bonds.
When the five member ring contains two double bonds, however, then either of Ar1 or Ar2 is pyridyl and the following compounds are excluded from this invention: 3-(2-Pyridyl)-5-(2-nitrophenyl)-1,2,4-oxadiazole, 3-(2-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(4-chlorophenyl)-1,2,4-oxadiazole, 3-(2-Pyridyl)-5-(3-methoxyphenyl)-1,2,4-oxadiazole, 3-(2-Pyridyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole, 3-(2-Pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole, 3-(2-chlorophenyl)-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethoxyphenyl)-5-(3-pyridyl)-1,2,4-oxadiazole, 3-styryl-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(3-Pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole,3-(3-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole, 3-(3-Pyridyl)-5-(2-pyridyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(3-pyridyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(2-hydroxyphenyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(4-chlorophenylmethyl)-1,2,4-oxadiazole, 3-(2-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole, 3-(2-pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole, 3-(3-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole, 3-(3-pyridyl)-5-(4-aminophenyl) -1,2,4-oxadiazole, 3-(2-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole, 3-(4-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole, 3-(2-pyridyl)-5-phenyl-1,2,4-oxadiazole, 2-(4-methoxyphenyl) -4-(2-pyridyl)-1,3-oxazole, 3-(2-pyridyl)-5-(2-chlorophenyl)-1,2,4,-triazole, 3-(2-pyridyl)-5-(2,6-dichlorophenyl)-1,2,4,-triazole, 2-(2-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy)phenyl]-furan, 2-(3-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy)phenyl]-furan, or 2-(4-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxyphenyl)]-furan. This proviso excludes known compounds that coincidentally contain structural features that are common to elements of general formula Ar1xe2x80x94Lxe2x80x94Ar2 or Formula I. Although none of these known compounds has been recognized heretofore as a metabotropic glutamate receptor antagonist, a subset of these is implicated in the literature as active agents in pharmaceutical compositions. These include: 3-(2-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole, 3-(3-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(4-chlorophenyl)-1,2,4-oxadiazole, 3-(2-chlorophenyl)-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethoxyphenyl)-5-(3-pyridyl)-1,2,4-oxadiazole, 3-styryl-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(3-Pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole, 3-(3-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(4-chlorophenoxymethyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(3-pyridyl)-1,2,4-oxadiazole, 3-(4-Pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(2-hydroxyphenyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole, 3-(2-ethyl-4-pyridyl)-5-(4-chlorophenylmethyl)-1,2,4-oxadiazole, 3-(2-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole, 3-(2-pyridyl)-5-(4-aminophenyl)-1,2,4-oxadiazole, 3-(3-pyridyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole, 3-(3-pyridyl)-5-(4-aminophenyl) -1,2,4-oxadiazole, 3-(2-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole, 3-(4-pyridyl)-5-{2-[2-(N,N,dimethylamino)-ethyl]oxyphenyl}-1,2,4-oxadiazole2-(2-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy) phenyl]-furan, 2-(3-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxy)phenyl]-furan, and 2-(4-pyridyl)-5-[3-(3-methoxy-4-cyclopentoxyphenyl)]-furan. Such compounds are excluded from the pharmaceutical composition of the present invention.
In embodiments of the invention, variables X, Y, and Z are independently selected from N, O, S, and substituted carbon, designated CRi, wherein Ri is as defined above. At least one of X, Y, or Z must be a heteroatom. In a preferred embodiment of the invention more than one of X, Y, and Z are heteroatoms. In one aspect of the invention two of X, Y, and Z are heteroatoms, while in another aspect of the invention all three of X, Y, and Z are heteroatoms. In a preferred embodiment of the invention at least one of X, Y, and Z, is N. In a more preferred embodiment of the invention two of X, Y and Z are N. In a further preferred embodiment of the invention, X is N, Y is N and Z is O.
According to a further aspect of the invention the groups Ar1 and Ar2 are independently selected from aryl and heteroaryl. Particular embodiments of the invention include those wherein Ar1 and Ar2 are independently selected from 5- and 6-member aryl and heteroaryl rings. In more particular embodiments of the invention Ar1 and Ar2 are selected from 6-member aryl and heteroaryl rings. Still more particular embodiments of the invention include those where Ar1 and Ar2 are independently selected from phenyl, pyridyl, furanyl, thienyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl. In a preferred embodiment of the invention, Ar1 is selected from phenyl and pyridyl. In a more preferred embodiment of the invention, Ar1 is selected from pyridyl. In an even more preferred embodiment, Ar1 is selected from 2-pyridyl. In another preferred embodiment, Ar2 is selected from phenyl and pyridyl. In a suitable embodiment, Ar2 is phenyl. In another suitable embodiment, Ar2 is 3-pyridyl.
According to another aspect of the invention at least one of Ar1 and Ar2 is substituted with at least one substituent G. In preferred embodiments of the invention, Ar2 is substituted with G. Suitable embodiments of the invention include those where G is selected from the group consisting of: haloalkyl; heteroaryl; cycloalkene; alkenyl; alkynyl; A-alkenyl; A-alkynyl; alkyloxy; A-alkyloxy; R2OR3; xe2x80x94R2OC(O)R3; (CH2)mxe2x80x94NR2R3; xe2x80x94OCH2CH(Cl)CH2Cl; and substituted aryl, wherein R2 and R3 are as defined above.
In one embodiment of the invention, G is haloalkyl.
In another embodiment of the invention, G is heteroaryl wherein heteroaryl is selected from the group consisting of: pyridyl; furanyl; thienyl; pyrazinyl; pyrimidinyl; pyridazinyl; pyrrolyl; pyrazolyl; imidazolyl; triazolyl; and thiazolyl. In a preferred embodiment of the invention, G is selected from the group consisting of: pyridyl; furanyl; thienyl; and pyrimidinyl. In a more preferred embodiment of the invention, G is selected from the group consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 3-thienyl; 5-pyrimidinyl; and 3-furanyl.
In yet another preferred embodiment of the invention, G is cycloalkene. In a further preferred embodiment of the invention G is selected from 5- and 6- member carbocyclic and heterocyclic rings containing one or more double bonds. In a still further preferred embodiment of the invention, G is a 6-member herterocyle containing one double bond. In yet a further embodiment, G is 3-(1,2,5,6-tetrahydropyridyl). In a suitable embodiment G, is N-substituted 3-(1,4,5,6-tetrahydropyridyl, for example 3-N-benzyl-(1,2,5,6-tetrahydropyridyl).
According to another aspect of the invention, G is alkenyl. In a more particular embodiment of the invention, G is selected from the group consisting of: vinyl; 2-methylvinyl; propenyl; and butenyl.
According to another aspect of the invention, G is alkynyl. In a more particular embodiment of the invention, G is selected from propargyl and butynyl.
According to yet another aspect of the invention, G is selected from the group consisting of: A-alkenyl; and A-alkynyl; wherein an alkenyl, or alkynyl, respectively, is linked to Ar1 or Ar2 though A. In particular embodiments of the invention, A is selected from the group consisting of: CH2O; NH; S; SO; SO2 ; NSO2; OSO2 ; and xe2x80x94C(NR2)NR3. In a more particular embodiment of the invention, A is selected from Oand NH. In a still more particular embodiment of the invention, G is xe2x80x94OHCH2CHxe2x95x90CH2.
In a still further embodiment of the invention, G is selected from the group consisting of: alkyloxy; and A-alkyloxy; wherein alkyloxy is a straight or branched chain alkyl radical substituted with a hydroxy group and A is a linker. In a more particular embodiment of the invention the alkyloxy group is linked to Ar1 or Ar2 through A, and A is selected from the group consisting of: CH2O; NH; S; SO; SO2 ; NSO2; OSO2 ; and xe2x80x94C(NR2)NR3. In a more particular embodiment of the invention, A is 0, and alkyloxy is selected from hydroxymethyl, hydroxyethyl, and hydroxypropyl. In a more particular embodiment G isxe2x80x94OCH2CH2CH2OH.
In a further embodiment of the invention, G is R2OCOR3. In a particular embodiment of the invention, G is an alkylester, wherein the ester links to Ar1 or Ar2 through an alkyl group. In a more particular embodiment of the invention, G is xe2x80x94CH2OC(O)H.
In still a further embodiment of the invention, G is (CH2)mxe2x80x94NR2R3, wherein m is 0 or 1. In a particular embodiment of the invention, G is (CH2)mxe2x80x94NR2R3, and R2 and R3 are independently selected from H, alkyl, alkyloxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, haloaryl, alkyloxyaryl, alkenylaryl, alkenyloxyaryl, haloheteroaryl. In a more particular embodiment of the invention, R2 and R3 are independently selected from H, and alkyl. In a further embodiment of the invention, R2 and R3 are independently selected from H and methyl.
According to another aspect of the invention, G is aryl substituted with a substituents R4. In particular, the aryl group is selected from the group consisting of: phenyl; naphthyl; anthrenyl; and fluorenyl. The substituent R4 is selected from the group consisting of: halo; xe2x80x94OR2; xe2x80x94SR2; xe2x80x94SOR2; xe2x80x94SO2R2; xe2x80x94SO2NR2R3; xe2x80x94R2OR3; R2SR3; xe2x80x94OCOR2; xe2x80x94OCONR2R3; xe2x80x94NR2COR3; xe2x80x94NR2CO2R3; xe2x80x94CN; xe2x80x94NO2; OH; xe2x80x94R2OH; xe2x80x94C(NR2)NR3; xe2x80x94CO2R2R3; xe2x80x94CONR2R3xe2x80x2; xe2x80x94C(O)R2; xe2x80x94CH(OR2)R3; xe2x80x94CH2(OR2); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR2R3; NR2R3; aryl; aralkyl; heteroaryl; and heteroaralkyl. In a preferred embodiment, aryl is phenyl. In a further preferred embodiment, R4 is selected from the group consisting of halo; NR2R3; alkoxy; and CN. In a further preferred embodiment of the invention, R4 is selected from the group consisting of F; NH2; methoxy.
According to another aspect of the invention, each of Ar1, Ar2, and G is optionally further substituted with one or more substituents selected from R2 and R4. In a preferred embodiment of the invention, Ar1 is further substituted with a substituent selected from the group consisting of: H; alkyl; haloalkyl; alkyloxy; alkylamine; halo; xe2x80x94OR2; xe2x80x94SR2; xe2x80x94SOR2; xe2x80x94SO2R2; xe2x80x94SO2NR2R3; xe2x80x94R2OR3; R2SR3; xe2x80x94OCOR2; xe2x80x94OCONR2R3; xe2x80x94NR2COR3; xe2x80x94NR2CO2R3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(NR2)NR3; xe2x80x94CO2R2R3; xe2x80x94CONR2R3; xe2x80x94C(O)R2; xe2x80x94CH(OR2)R3; xe2x80x94CH2(OR2); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR2R3; NR2R3; aryl; aralkyl; heteroaryl; heteroaralkyl; cycloalkyl; heterocycloalkyl; alkylaryl; alkylheteroaryl; haloaryl; alkyloxyaryl; alkenylaryl; alkenyloxyaryl; and haloheteroaryl. In a further preferred embodiment of the invention, Ar1 is is further substituted with a substituent selected from the group consisting of: halo and cyano.
In another aspect of the invention wherein Ar1 is 2-pyridyl, the further substituent is located at the 5-position of Ar1. In a further embodiment of the invention, Ar1 is 5-fluoro-2-pyridyl. In yet another embodiment of the invention, Ar1 is 5-cyano-2-pyridyl.
According to a further aspect of the invention, Ar2 is further substituted with one or more substituents selected from the group consisting of: H; alkyl; haloalkyl; alkyloxy; alkylamine; halo; xe2x80x94OR2; xe2x80x94SR2; xe2x80x94SOR2; xe2x80x94SO2R2; xe2x80x94SO2NR2R3; xe2x80x94R2OR3; xe2x80x94R2SR3; xe2x80x94OCOR2; xe2x80x94OCONR2R3; xe2x80x94NR2COR3; xe2x80x94NR2CO2R3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(NR2)NR3; xe2x80x94CO2R2R3; xe2x80x94CONR2R3; xe2x80x94C(O)R2; xe2x80x94CH(OR2)R3; xe2x80x94CH2(0R2); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR2R3; NR2R3; aryl; aralkyl; heteroaryl; heteroaralkyl; cycloalkyl; heterocycloalkyl; alkylaryl; alkylheteroaryl; haloaryl; alkyloxyaryl; alkenylaryl; alkenyloxyaryl; and haloheteroaryl. In a preferred embodiment of the invention, Ar2 is further substituted with one or more substituents selected from the group consisting of: alkyl; alkoxy; alkyloxy; hydroxy; halo; cyano; and nitro. In a more preferred embodiment of the invention Ar2, has a further substituent selected from the group consisting of: cyano; fluoro; chloro; bromo; iodo; and methoxy.
In a more preferred embodiment of the invention, Ar2 is phenyl or 3-pyridyl, and is substituted with the substituent G at the meta position and a further substituent at the other meta position.
In another embodiment of the invention, the substituent G is optionally further substituted with one or more substituents selected from the group consisting of: H; alkyl; haloalkyl; alkyloxy; alkylamine; halo; xe2x80x94OR2; xe2x80x94SR2; xe2x80x94SOR2; xe2x80x94SO2 R2; xe2x80x94SO2NR2R3; xe2x80x94R2OR3 R2SR3; xe2x80x94OCOR2; xe2x80x94OCONR2R3; xe2x80x94NR2COR3; xe2x80x94NR2CO2R3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(NR2)NR3; xe2x80x94CO2R2R3; xe2x80x94CONR2R3; xe2x80x94C(O)R2; xe2x80x94CH(OR2)R3; xe2x80x94CH2(0R2); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR2R3; NR2R3; aryl; aralkyl; heteroaryl; heteroaralkyl; cycloalkyl; heterocycloalkyl; alkylaryl; alkylheteroaryl; haloaryl; alkyloxyaryl; alkenylaryl; alkenyloxyaryl; and haloheteroaryl. In a more preferred embodiment of the invention, G is optionally further substituted with one or more substituents selected from the group consisting of: alkyl; alkoxy; alkenyl; halo; and cyano. In a particular G is xe2x80x94OCH2CH2CH2OH, and is further substituted with chloro, to give xe2x80x94OCH2CH(Cl)CH2OH.
In one aspect of the invention, specific compounds of formula I include:
3-(2-pyridyl)-5-(3-methoxyphenyl)-1,2,4-oxadiazole (B1),
3-(2-pyridyl)-5-(3,5-dichlorophenyl)-1,2,4-oxadiazole (B2),
3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (B3),
3-(2-pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole (B5),
3-(2-pyridyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (B6),
3-(2-pyridyl)-5-(3-methylphenyl)-1,2,4-oxadiazole (B9),
3-(2-pyridyl)-5-(1-naphthyl)-1,2,4-oxadiazole (B10),
3-(2-pyridyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole (B11),
3-(2-pyridyl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole (B16),
3-(2-pyridyl)-5-(2,5-difluorophenyl)-1,2,4-oxadiazole (B17),
3-(2-pyridyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole (B18),
3-(2-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B21),
3-(2-pyridyl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol (B23),
3-(2-pyridyl)-5-(2,3-dichlorophenyl)-1,2,4-oxadiazole (B25),
3-(2-pyridyl)-5-(3-chloro-5-cyanophenyl)-1,2,4-oxadiazole (B26),
3-(2-pyridyl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole (B27),
3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole (B28),
3-(5-chloropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B29) 3-(5-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B30),
3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B31),
3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B32),
3-(5-fluoropyrid-2-yl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazole (B33),
3-(5-methoxypyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B34),
3-(2-quinolinyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B35),
3-(3-chloro-5-trifluoro methylpyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B36),
3-(2-pyridyl)-5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazole (B37),
3-(2-pyridyl)-5-(2-chloro-5-methylthiophenyl)-1,2,4-oxadiazole (B39),
3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole (B42),
3-(2-pyridyl)-5-(2,5,6-trifluorophenyl)-1,2,4-oxadiazole (B45),
3-(2-pyridyl)-5-(3-nitrophenyl)-1,2,4-oxadiazole (B19),
3-(2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B22), and pharmaceutically acceptable salts thereof.
In a further aspect of the invention, specific compounds of Formula I include:
2-(3,5-dichlorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-chlorophenyl)-4-(2-pyridyl)-1,3-oxazole (B50),
2-(3-methoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(2-chlorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-trifluorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-methylphenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(1-naphthyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-trifluoromethoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(2,3-difluorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(2,5-difluorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3,5-difluorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-cyanophenyl)-4-(2-pyridyl)-1,3-oxazole (B52),
2-(3,5-dimethoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(2,3-dichlorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-chloro-5-cyanophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-fluoro-5-cyanophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-chloro-5-fluorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-c yanophenyl)-4-(5-chloropyrid-2-yl)-1,3-oxazole,
2-(3-cyanophenyl)-4-(5-fluoropyrid-2-yl)-1,3-oxazole,
2-(3-cyano-5-fluorophenyl)-4-(5-fluoropyrid-2-yl)-1,3-oxazole,
2-(3-cyanophenyl)-4-(3-fluoropyrid-2-yl)-1,3-oxazole,
2-(3,5-dimethoxyphenyl)-4-(5-fluoropyrid-2-yl)-1,3-oxazole,
2-(3-cyano phenyl)-4-(5-meth oxy pyrid-2-yl)-1,3-oxazole,
2-(3-cyanophenyl)-4-(2-quinolinyl)-1,3-oxazole,
2-(3-cyanophenyl)-4-(3-chloro-5-trifluoromethylpyrid-2-yl)-1,3-oxazole,
2-(5-chloro-2-methoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(2-chloro-5-methylthiophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(2-bromo-5-methoxyphenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(2,5,6-trifluorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-[3-chlorophenyl]-4-[pyridin-2-yl]-1,3-oxazole,
2-(2,5,6-trifluorophenyl)-4-(2-pyridyl)-1,3-oxazole,
2-(3-nitrophenyl)-4-(2-pyridyl-1,3-oxazole,
2-(3-bromophenyl)-4-(2-pyridyl)-1,3-oxazole (B51) and pharmaceutically acceptable salts thereof.
In still a further aspect of the invention, the compounds of the formula I include:
3-(2-Pyridyl)-5-(3-allyloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (B77),
3-(2-Pyridyl)-5-(3-N,N-dimethylaminophenyl)-1,2,4-oxadiazole (B82),
3-(2-Pyridyl)-5-(3-cyano-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole (B101),
3-(2-Pyridyl)-5-[2-methoxy-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole (B102),
3-(2-pyridyl)-5-[2-fluoro-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole (B103),
3-(2-Pyridyl)-5-(3-fluoro-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole (B104),
3-(2-Pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (B105),
3-(2-Pyridyl)-5-[2-fluoro-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole (B106),
3-(2-Pyridyl)-5-[2-methoxy-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole (B107),
3-(2-Pyridyl)-5-(3-cyano-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (B108),
3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (B109),
3-(2-Pyridyl)-5-[5-(3-pyridyl-pyrid-3-yl)]-]-1,2,4-oxadiazole (B111),
3-(5-Fluoropyrid-2-yl)]-5-[5-(3-pyridyl-pyrid-3-yl)]-]-1,2,4-oxadiazole (B110),
3-(5-Cyanopyrid-2-yl)-5-(3-(pyrid-3-yl)phenyl)-1,2,4-oxadiazole (B112),
3-(5-Cyanopyrid-2-yl)-5-(3-fluoro-5-(pyrid-3-yl)phenyl)-1,2,4-oxadiazole (B113),
3-(2-Pyridyl)-5-(3-cyano-5-(2-pyridyl)phenyl)-1,2,4-oxadiazole (B124),
3-(2-Pyridyl)-5-[2-methoxy-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole (B125),
3-(-2-Pyridyl)-5-[2-fluoro-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole (B126),
3-(2-Pyridyl)-5-[(3-(3-fuorophenyl)-5-fluorophenyl)]-1,2,4-oxadiazole (B114),
3-(2-Pyridyl)-5-(3-cyano-5-(3-thiophene)phenyl)-1,2,4-oxadiazole (B115),
3-(2-Pyridyl)-5-[5-(3-thienyl)-pyrid-3-yl]-1,2,4-oxadiazole (B116),
3-(2-Pyridyl)-5-[5-(3-furyl)-pyrid-3-yl)-1,2,4-oxadiazole (B117),
3-(2-Pyridyl)-5-[5-(3-methoxyphenyl)-pyrid-3-yl]-1,2,4-oxadiazole (B119),
3-(2-Pyridyl)-5-(3-cyano-5-(5-pyrimidyl)phenyl)-1,2,4-oxadiazole (B120),
3-(2-Pyridyl)-5-(3-cyano-5-(3-aminophenyl)phenyl)-1,2,4-oxadiazole (B121),
3-(2-Pyridyl)-5-(3-cyano-5-(3-fluorophenyl)phenyl)-1,2,4-oxadiazole (B122),
3-(2-Pyridyl)-5-[5-(5-pyrimidyl)-pyrid-3-yl]-1,2,4-oxadiazole (B123),
3-(2-Pyridyl)-5-(3-aminomethyl-5-cyanophenyl)-1,2,4-oxadiazole (B127),
3-(2-Pyridyl)-5-[5[(2-propenyl)-pyrid-3-yl]-1,2,4-oxadiazole (B128),
3-(2-Pyridyl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole (B129),
3-(2-Pyridyl)-5-(3-cyano-5-(2-hydroxyethyl)phenyl)-1,2,4-oxadiazole (B130),
3-(2-Pyridyl)-5-(3-cyano-5-(2,3-dichloropropoxy)phenyl)-1,2,4-oxadiazole (B131),
3-(2-Pyridyl)-5-(3-allyloxy-5-carboxyphenyl)-1,2,4-oxadiazole (B135),
3-(2-Pyridyl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole (B136),
3-(2-Pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl] phenyl)-1,2,4-oxadiazole (B142),
3-(2-Pyridyl)-5-(2-N-methylaminophenyl)-1,2,4-oxadiazole (B144), and
3-(2-Pyridyl)-5-[5-(3-N-benzyl-1,2,5,6,tetrahydropyridine)-pyrid-3-yl]-1,2,4-oxadiazole (B143), and pharmaceutically acceptable salts thereof.
In yet a further aspect of the invention, the following compounds of Formula I are provided:
3-(5-Methyl-pyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B57),
3-(5-Cyano-pyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (B58),
3-(2-Pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (B62),
3-(2-Pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (B63),
3-(2-Pyridyl)-5-(5-cyano-2-fluorophenyl)-1,2,4-oxadiazole (B64),
3-(2-Pyridyl)-5-(5-bromopyrid-3-yl)-1,2,4-oxadiazole (B65),
3-(2-Pyridyl)-5-(5-chloro-pyrid-3-yl)-1,2,4-oxadiazole (B66),
3-(5-Cyanopyrid-2-yl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (B67),
3-(5-Fluoropyrid-2-yl)-5-(5-bromo-pyrid-3-yl-1,2,4-oxadiazole (B68),
3-(2-Pyridyl)-5-(2-thiomethoxy-pyrid-3-yl)]-1,2,4-oxadiazole (B69),
3-(2-Pyridyl)-5-(5-methylpyrid-3-yl)-1,2,4-oxadiazole (B70),
3-(2-Pyridyl)-5-(5-methoxypyrid-3-yl)-1,2,4-oxadiazole (B72),
3-(2-Pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole (B73),
3-(2-Pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole (B74),
3-(2-Pyridyl)-5-(3-iodo-5-bromophenyl)-1,2,4-oxadiazole (B75),
3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole (B76),
3-(2-Pyridyl)-5-(3-iodo-5-(methylphenylester)-1,2,4-oxadiazole (B78),
3-(2-Pyridyl)-5-(3-methoxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (B79),
3-(2-Pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (B80),
3-(2-Pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (B81),
3-(5-Cyano-2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole (B59),
3-(5-Cyano-2-pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B60),
3-(5-Cyano-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (B61),
3-(2-Pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole (B97),
3-(2-Pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B98),
3-(2-Pyridyl)-5-(5-cyano-pyrid-3-yl)-1,2,4-oxadiazole (B99),
3-(2-Pyridyl)-5-(3-cyano-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (B100),
3-(2-Pyridyl)-5-(5-phenyl-pyrid-3-yl)-1,2,4-oxadiazole (B118),
3-(2-Pyridyl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B134),
3-(2-Pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (B137),
3-(2-Pyridyl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole (B141),
2-(3-Cyanophenyl)-4-(pyridin-2-yl)-1,3-thiazole (B146),
2-(3-Bromo-5-iodophenyl)-4-pyridin-2-yl)-1,3-oxazole (B147),
2-(2-Pyridyl)-5-(3-iodophenyl)-1,3,4-oxadiazole (B148),
2-(2-Pyridyl)-5-(3-cyanophenyl)-1,3,4-oxadiazole (B149),
2-(2-Pyridyl)-5-(3-cyanophenyl)-1,3,4-triazole (B150),
3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B83),
3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B84),
3-(5-Chloropyrid-2-yl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole (B85),
3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B86),
3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B87),
3-(5-Fluoropyrid-2-yl)-5-(3-fluoro-5-chlorophenyl)-1,2,4-oxadiazole (B88),
3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B89),
3-(5-Cyanopyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole (B90),
3-(5-Cyanopyrid-2-yl)-5-(3-fluoro-5-chlorophenyl)-1,2,4-oxadiazole (B91)
3-(5-Cyanopyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole (B92),
3-(5-Fluoropyrid-2-yl)-5-(3,5-di-cyanophenyl)-1,2,4-oxadiazole (B93),
3-(3-(4-Dimethylaminobutoxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B94),
3-(3-(5-Dimethylaminopentyloxy)-pyrid-2-yl)-5-(3-Cyano-5-fluorophenyl)-1,2,4oxadiazole (B95), and
[3-(3-(6-Dimethylaminohexyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (B96).
The present invention also provides compounds that are potent and selective antagonists of mGluR5, which may be represented by Formula II. 
According to another aspect of the invention there is a five member ring containing two variables X2, and Y2. There are attached to this five member ring two substituents, Ar3 and Ar4. The five member ring may contain 0, 1, or 2 double bonds as denoted by the dotted lines in Formula II. In a preferred embodiment of the invention, the five member ring has two double bonds.
In embodiments of the invention, the variable X2 is selected from the group consisting of: N and C, and the variable Y2 is selected from the group consisting of: N; O; S; and CR5, wherein at least one of X2, and Y2 must be a heteroatom. In the case where Y2 is CR5, R5 is selected from the group consisting of: H; alkyl; xe2x80x94CF3; xe2x80x94OR6; xe2x80x94SR6; NR6R7; xe2x80x94C(O); xe2x80x94C(S); xe2x80x94Cxe2x95x90NR6; and xe2x95x90CR6R7, wherein R6 and R7 may be independently selected from the group consisting of: H; alkyl; haloalkyl; alkyloxy; alkylamine; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; alkylaryl; alkylheteroaryl; haloaryl; alkyloxyaryl; alkenylaryl; alkenyloxyaryl; and haloheteroaryl. In preferred embodiments of the invention, both X2 and Y2 are heteroatoms. In a further preferred embodiment of the invention, X2 is N. In a still more preferred embodiment of the invention Y2 is N. In a more preferred embodiment of the invention, X2 and Y2 are both N.
According to another aspect of the invention, the group Ar3 and Ar4, are independently selected from the group consisting of aryl and heteroaryl. Particular embodiments of the invention include those wherein Ar3 and Ar4 are independently selected from 5- and 6-member aryl and heteroaryl rings. In more particular embodiments of the invention, Ar3 and Ar4 are selected from 6-member aryl and heteroaryl rings. Still more particular embodiments of the invention include those where Ar3 and Ar4 are independently selected from phenyl, pyridyl, furanyl, thienyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, and thiazolyl. In a preferred embodiment of the invention, Ar3 and Ar4 are independently selected from phenyl and pyridyl. In a more preferred embodiment of the invention, one of Ar3 and Ar4 is phenyl and one is pyridyl.
According to still a another embodiment of the invention, Ar3 and Ar4 are optionally substituted with one or more substituents G2, wherein G2 is selected from the group consisting of: haloalkyl; heteroaryl; cycloalkene; alkenyl; alkynyl; A-alkenyl; A-alkynyl; alkyloxy; A-alkyloxy; xe2x80x94R6OR7; xe2x80x94R6OC(O)R7; (CH2)mxe2x80x94NR6R7; xe2x80x94OCH2CH(Cl)CH2Cl; and substituted aryl wherein the aryl substituent is R8. In a particular embodiment wherein one, or both, of Ar3 and Ar4 are substituted with G2, G2 is selected from the group consisting of: A-alkenyl; Alkynyl; and A-alkyloxy, and A is selected from the group consisting of: CH2O; NH; S; SO; SO2 ; OSO2 ; NSO2; and xe2x80x94C(NR6)NR7. In a more particular embodiment, G2 is (CH2)mxe2x80x94NR6R7. In an embodiment of the invention, G2 is substituted aryl and the substituent R8 is selected from the group consisting of: halo; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94SOR6; xe2x80x94SO2R6; xe2x80x94SO2NR6R7; xe2x80x94R6OR7 R6SR7; xe2x80x94OCOR6; xe2x80x94OCONR6R7; xe2x80x94NR6COR7; xe2x80x94NR6CO2R7; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(NR6)NR7; xe2x80x94CO2R6R7; xe2x80x94CONR6R7; xe2x80x94C(O)R6; xe2x80x94CH(OR6)R7; xe2x80x94CH2(OR6); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR6R7; NR6R7; aryl; aralkyl; heteroaryl; and heteroaralkyl.
In a further embodiment of the invention, each of Ar3 and Ar4 and G2 is further substituted with one or more substituents selected from R6, and R8. In a preferred embodiment of the invention, each of Ar3 and Ar4 is independently further substituted with one or more substituents selected from the group consisting of: H; alkyl; haloalkyl; alkyloxy; alkylamine; halo; xe2x80x94OR6; xe2x80x94SR6; xe2x80x94SOR6; xe2x80x94SO2 R6; xe2x80x94SO2NR6R6; xe2x80x94R6OR7 R6SR7; xe2x80x94OCOR6; xe2x80x94OCONR6R7; xe2x80x94NR6COR7; xe2x80x94NR6CO2R7; xe2x80x94CN; xe2x80x94NO2; xe2x80x94C(NR6)NR7; xe2x80x94CO2R6R7; xe2x80x94CONR6R7; xe2x80x94C(O)R6; xe2x80x94CH(OR6)R7; xe2x80x94CH2(0R6); xe2x80x94Axe2x80x94(CH2)mxe2x80x94NR6R7; NR6R7; aryl; aralkyl; heteroaryl; heteroaralkyl; cycloalkyl; heterocycloalkyl; alkylaryl; alkylheteroaryl; haloaryl; alkyloxyaryl; alkenylaryl; alkenyloxyaryl; and haloheteroaryl.
According to a further aspect of the invention, Ar3 and Ar4 are independently substituted with a substituent selected from the group consisting of halo and cyano.
In specific embodiments of the invention, the compounds of formula II include:
4-(3-Cyanophenyl)-1-(2-pyridyl)-1H-imidazole (B151)
1-(3-Cyanophenyl)-4-(2-pyridyl)-1H-imidazole (B152).
The pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art, for example, see Aramori et al., Neuron 8:757 (1992); Tanabe et al., Neuron 8:169 (1992); Miller et al, J. Neuroscience 15: 6103 (1995); Balazs, et al., J. Neurochemistry 69:151 (1997). The methodology described in those publications is incorporated herein by reference.
Conveniently, the compounds of the invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca2+]i in cells expressing mGluR5 that can bind the compounds. A well-known cell line which is suitable for this purpose is described in Miller et al., J. Neuroscience 15: 6103 (1995), the contents of which are hereby incorporated by reference. It has been shown that exposure to rat astrocytes to the growth factors, basic fibroblast growth factor, EGF, or transforming growth factor-xcex1 markedly increased the protein expression and functional activity of endogenous mGluR5 (Miller et al., J. Neuroscience, 15(9): 6103-6109, 1995).
In brief, primary astrocyte cultures were prepared from 3-5 day old Sprague-Dawley rat pups using a modification of Miller et al. were plated on poly-L lysine coated flasks in Dulbecco""s modified Eagle""s medium (DMEM) containing fetal calf serum (FCS). For cuvette analysis, cultures were up-regulated with growth factors in flasks for 3-5 days, then harvested and prepared for measurement of [Ca2+]i mobilization as previously described (Nemeth et al., 1998).
For FLIPR analysis, cells were seeded on poly-D lysine coated clear bottom 96-well plates with black sides and analysis of [Ca2+]i mobilization was performed 3 days following the growth factor up-regulation.
FLIPR experiments were done using a laser setting of 0.800 W and a 0.4 second CCD camera shutter speed. Each FLIPR experiment was initiated with 180 xcexcL of buffer present in each well of the cell plate. After each addition of compound, the fluorescence signal was sampled 50 times at 1 second intervals followed by 3 samples at 5 second intervals. Responses were measured as the peak height of the response within the sample period.
EC50 and IC50 determinations were made from data obtained from 8 point concentration response curves (CRC) performed in duplicate. Agonist CRC were generated by scaling all responses to the maximal response observed for the plate. Antagonist block of the agonist challenge was normalized to the average response of the agonist challenge in 14 control wells on the same plate. A detailed protocol for testing the compounds of the invention is provided below at Example 11.
The compounds of the present invention may be useful for treating neurological disorders or diseases. While these compounds typically will be used in therapy for human patients, they also can be used in veterinary medicine, to treat similar or identical diseases.
In therapeutic and/or diagnostic applications, the compounds of the invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in REMINGTON""S PHARMACEUTICAL SCIENCES (18th ed.), Mack Publishing Co. (1990).
The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.01 to about 1000 mg, preferably from about 0.5 to about 100 mg, per day may be used. A most preferable dosage is about 2 mg to about 70 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/disphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found, for example, in REMINGTON""S PHARMACEUTICAL SCIENCES (18th ed.), supra.
Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate.
Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-release form as is known to those skilled in the art. Techniques for formulation and administration may be found in REMINGTON""S PHARMACEUTICAL SCIENCES; (18th ed.), supra. Suitable routes may include oral, buccal, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, inter alia.
For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank""s solution, Ringer""s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the compositions of the present invention, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.
The present invention will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
Tables 1, 2, and 3 summarize specific exemplified compounds of the present invention.
Preparation of mGluR Group I Antagonists
Many starting materials for preparing the compounds of the present invention are available from commercial sources, such as Aldrich Chemical Company (Milwaukee, Wis.). Moreover, compounds of the invention are readily prepared, from available precursors, using straightforward transformations which are well known in the art. The skilled artisan will recognize that mGluR Group I antagonists, according to the invention, can be prepared via methodology that is well known, using widely recognized techniques of organic chemistry. Suitable reactions are described in standard textbooks of organic chemistry. For example, see March, ADVANCED ORGANIC CHEMISTRY, 2d ed., McGraw Hill (1977).
More specifically, compounds of the invention generally can be prepared by formation of the G moiety between two precursor compounds containing suitable Ar1 and Ar2 moieties. When the linker contains a 1,2,4-oxadiazole, the heterocycle may be formed using well known techniques, such as reaction between an amidoxime and an acid chloride, or by the reaction of an amidoxime and an acylimidazole. An illustration of such a transformation is provided in Examples 4 and 5, below.
Amidoximes can be prepared using well known techniques by the reaction of an Ar1 substituted nitrile with hydroxylamine. An illustration of such a transformation is provided below in Example 1.
In most cases, the precursor Ar2 acid chlorides are readily available, or may be prepared using straightforward techniques of organic chemistry. For example, carboxylic acids may be converted into the corresponding acid chlorides by reaction with, for example, thionyl chloride or oxalyl chloride.
In the case where the linker contains a 1,3-oxazole, compounds were prepared using a procedure similar to that given by Kelly et al., J. Org. Chem. 61, 4623-4633 (1996). Thus, 3,5-disubstituted-1,3-oxazoles were prepared by mixing a haloketone with carboxamide in refluxing toluene for 3 days. The resulting mixture was allowed to cool to room temperature, the solvent was removed and the residue was purified.
Scheme 1 illustrates a method for synthesizing compounds of the present invention. In particular, the method illustrated by scheme 1 is used for making the following exemplified compounds: B77-B81, B86, B89, B101, B108, B115, B120-B122, B124, B129-B141. 
Scheme 2 illustrates another method for synthesizing compounds of the present invention. In particular, the method of scheme 2 is used to make the exemplified compound B144. 
Scheme 3 illustrates a further method for synthesizing compounds of the present invention. In particular, the method of scheme 3 is used to make the following exemplified compounds: B57-B76, B82-B85, B87, B88, B90, B91, B93-B100, B102-B107, B109-B114, B116-B119, B123, B125-B128, B142, B143. 
Other compounds of the present invention may readily be prepared by modifications to the reactions exemplified in the Schemes above, as will be appreciated by the skilled artisan.